The combination of both polar and apolar segments in a molecule allows the manipulation of immiscible liquids in a manner that is applicable to a wide variety of processes: ranging from the use of detergents for environmental clean up activities to the processing of foods. In the pharmaceutical industry, the formulation of drugs that are immiscible with water is often fraught with failure [1, 2] despite the availability of amphiphilic compounds with approved excipient status [3]. However, ensuring sufficient bioavailability from drugs with poor aqueous solubility, i.e. hydrophobic drugs, is of great importance in drug development. Drugs with poor aqueous solubility are defined by the British Pharmacopoeia as “very slightly soluble” and such drugs have an aqueous solubility of less than 1 mg per milliliter of solvent (Medicines Commission, British Pharmacopoeia, The Stationary Office, London, 2002)
Bioavailability of hydrophobic drugs has been improved in the past by the addition of block copolymers [14-18]. It is known that both block copolymer and grafted polymer amphiphiles self assemble into polymeric micelles [5, 22], vesicles [23, 24] and dense amorphous nanoparticles [22, 25, 26]. Block copolymer micelles are conventional single micelle entities with a diameter of 12-36 nm [29, 30].
Micellar phases have been used to solubilise drugs in aqueous media and the stability of the drug solubilising micellar core, according to the phase separation model is a function of its critical micellar concentration (CMC, Equation 1)—the concentration at which micellar aggregates begin to form.ΔGmicelle0=RT1nXcmc where ΔGmicelle0=the standard free energy of micellisation, R=the gas constant, T=temperature and Xcmc=the critical micelle concentration in mole fraction units. A lower CMC thus favours micellisation.
Pharmaceutically approved low molecular weight surfactants [4] and block copolymers [5-7] typically possess CMC values in the mM concentration range and are inefficient in carrying hydrophobic drugs as molar amphiphile/drug ratios are typically in excess of 10:1 and frequently extend to 1000:1 [4, 8-10]. The solubilisation of drugs within micellar cores for a fixed mole of solubilising micelle is dependent on the log P of the solubilisate [11], molecular volume of the solubilisate [11] and relative size of the hydrophobic nanodomain formed by the association colloid [12, 13]. A high log P/molar volume ratio favours partitioning into micelles and a large hydrophobic volume within the micelle favours the encapsulation of drugs within the micelle.
Increasing the hydrophobic volume of a particle by increasing the aggregation number of the individual monomers to yield larger particles is thus a possible means of increasing the level of drug that may be solubilised within colloidal aggregates. However care must be taken to avoid excessive aggregation which would lead to precipitation of the colloid forming molecules and the drug.
Previously, we have disclosed solubilising carbohydrate polymers and shown that they can be employed to formulate hydrophobic drugs which are added to an aqueous phase in the presence of the solubilising carbohydrate polymers (WO 04/026912). In the exemplified amphiphilic polymers disclosed in this application, the molar percentage of palmitoyl groups was between 3.0% and 8.2% and the molar percentage of, quaternary ammonium groups was between 7.9% and 19.0%.
However, there remains a continuing need in the art for further ways to formulate drugs to improve their delivery, in particular to increase the bioavailability of hydrophobic drugs.